This invention relates to a series of pyrazolo[4,3-d]pyrimidin-7-one compounds of formula I (as defined below) and intermediates thereof. More notably, most of the compounds of interest are inhibitors of type 5 cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate phosphodiesterase (CGMP PDE5) and have utility in a variety of therapeutic areas (such as male erectile dysfunction). A compound of particular interest is 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (hereinafter compound of formula IA).
xe2x80x9cProcesses for the preparation of compounds of formula I are disclosed in WO 01/27112. In particular, example 132 of WO 01/27112 discloses a displacement reaction for preparing compound IA.xe2x80x9d
According to a first aspect of the invention there is provided a process for the preparation of a compound of formula (I): 
or a pharmaceutically or veterinarily acceptable salt , pro-drug, polymorph and/or solvate thereof, wherein
Q represents O or NR5 
R1 represents H, lower alkyl, Het, alkylHet, aryl or alkylaryl (which latter five groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR6, OC(O)R7, C(O)R8, C(O)OR9, C(O)NR10R11, NR12R13 and SO2NR14R15)
R2 represents H, halo, cyano, nitro, OR6, OC(O)R7, C(O)R8, C(O)OR9, C(O)NR10R11, NR12R13, SO2NR14R15, lower alkyl, Het, alkylHet, aryl or alkylaryl (which latter five groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR6, OC(O)R7, C(O)R8, C(O)OR9, C(O)NR10R11, NR12R13 and SO2NR14R15)
R3 represents H, lower alkyl, alkylHet or alkylaryl (which latter three groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR6, OC(O)R7, C(O)R8, C(O)OR9, C(O)NR10R11, NR12R13 and SO2NR14R15)
R4 represents H, halo, cyano, nitro, halo(loweralkyl), OR6, OC(O)R7, C(O)R8, C(O)OR9, C(O)NR10R11, NR12R13, NR16Y(O)R17, N[Y(O)R17]2, SOR18, SO2R19, C(O)AZ, lower alkyl, lower alkenyl, lower alkynyl, Het, alkylHet, aryl, alkylaryl (which latter seven groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR6, OC(O)R7, C(O)R8, C(O)OR9, C(O)NR10R11, NR12R13 and SO2NR14R15)
Y represents C or S(O)
A represents lower alkylene
Z represents OR6, halo, Het or aryl (which latter two groups are both optionally substituted with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR6, OC(O)R7, C(O)R8, C(O)OR9, C(O)NR10R11, NR12R13 and SO2NR14R15)
R10 and R11 independently represent H or lower alkyl (which latter group is optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR6, OC(O)R7, C(O)R6, C(O)OR9, C(O)NR10R11, NR12R13, SO2NR14R15 and NR20S(O)2R21 or Het or aryl optionally substituted with one or more of said latter thirteen groups) or one of R10 and R11 may be lower alkoxy, amino or Het, which latter two groups are both optionally substituted with lower alkyl
R10a and R11a independently represent R10 and R11 as defined above, except that they do not represent groups that include lower alkyl, Het or aryl, when these three groups are substituted and/or terminated (as appropriate) by one or more substituents that include one or more C(O)NR10aR11a and/or NR12R13 groups
R12 and R13 independently represent H or lower alkyl (which latter group is optionally substituted and/or terminated with one or more substituents selected from OR6, C(O)OR9, C(O)NR22R23 and NR24R25), one of R12 or R13 may be C(O)-lower alkyl or C(O)Het (in which Het is optionally substituted with lower alkyl), or R12 and R13 together represent C3-7 alkylene (which alkylene group is optionally unsaturated, optionally substituted by one or more lower alkyl groups and/or optionally interrupted by O or NR26)
R14 and R15 independently represent H or lower alkyl or R14 and R15, together with the nitrogen atom to which they are bound, form a heterocyclic ring
R16 and R17 independently represent H or lower alkyl (which latter group is optionally substituted and/or terminated with one or more substituents selected from OR6, C(O)OR9, C(O)NR22R23 and NR24R25) or one of R16 and R17 may be Het or aryl, which latter two groups are both optionally substituted with lower alkyl
R5, R6, R7, R8, R9, R18, R19, R20, R22, R23, R24 and R25 independently represent H or lower alkyl
R18 and R19 independently represent lower alkyl
R21 represents lower alkyl or aryl
R28 represents H, lower alkyl, aryl, C(O)R27 or S(O)2R28 
R27 represents H, lower alkyl or aryl
R28 represents lower alkyl or aryl
Het represents an optionally substituted four- to twelve-membered heterocyclic group, which group contains one or more heteroatoms selected from nitrogen, oxygen, sulphur and mixtures thereof
said process comprising reacting a compound of formula (II), (III), (IV) or (V) in the presence of xe2x88x92OR3 and a hydroxide trapping agent or, alternatively, in the case of compounds of formulae (IV) or (V) reacting in the presence of an auxiliary base and a hydroxide trapping agent. An auxiliary base as defined herein means a base other than xe2x88x92OR3 which is used in place of xe2x88x92OR3. 
wherein X is a leaving group and Q and R1 to R4 are as defined above.
The term xe2x80x9carylxe2x80x9d, when used herein, includes six- to ten-membered carbocyclic aromatic groups, such as phenyl and naphthyl, which groups are optionally substituted with one or more substituents selected from aryl (which group may not be substituted by any further aryl groups), lower alkyl, Het, halo, cyano, nitro, OR6, OC(O)O)R7, C(O)O)R8, C(O)O)R9, C(O)NR10aR11a, NR12aR13a (wherein R12a and R13a independently represent R12 and R13 as hereinbefore defined, except that: (i) they do is not represent C(O)Het in which Het is substituted by one or more substituents that include one or more C(O)NR10aR11a and/or NR12aR13a, groups; or (ii) they do not together represent C3-7 alkylene interrupted by NR26) and SO2NR14R15.
The term xe2x80x9cHetxe2x80x9d, when used herein, includes four- to twelve-membered, preferably four- to ten-membered, ring systems, which rings contain one or more heteroatoms selected from nitrogen, oxygen, sulfur and mixtures thereof, and which rings may contain one or more double bonds or be non-aromatic, partly aromatic or wholly aromatic in character. The ring systems may be monocyclic, bicyclic or fused. Each xe2x80x9cHetxe2x80x9d group identified herein is optionally substituted by one or more substituents selected from halo, cyano, nitro, oxo, lower alkyl (which alkyl group may itself be optionally substituted or terminated as defined below), OR6, OC(O)R7, C(O)R8, C(O)OR9, C(O)NR10aR11a, NR12aR13a and SO2NR14R15. The term thus includes groups such as optionally substituted azetidinyl, pyrrolidinyl, imidazolyl, indolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridazinyl, morpholinyl, pyrimidinyl, pyrazinyl, pyridinyl, quinolinyl, isoquinolinyl, piperidinyl, pyrazolyl imidazopyridinyl and piperazinyl. Substitution at Het may be at a carbon atom of the Het ring or, where appropriate, at one or more of the heteroatoms.
xe2x80x9cHetxe2x80x9d groups may also be in the form of an N-oxide.
The heterocyclic ring that R14 and R15 (together with the nitrogen atom to which they are bound) may represent may be any heterocyclic ring that contains at least one nitrogen atom, and which ring forms a stable structure when attached to the remainder of the molecule via the essential nitrogen atom (which, for the avoidance of doubt, is the atom to which R14 and R15 are attached). In this respect, heterocyclic rings that R14 and R15 (together with the nitrogen atom to which they are bound) may represent include four- to twelve-membered, preferably four- to ten-membered, ring systems, which rings contain at least one nitrogen atom and optionally contain one or more further heteroatoms selected from nitrogen, oxygen and/or sulfur, and which rings may contain one or more double bonds or be non-aromatic, partly aromatic or wholly aromatic in character. The term thus includes groups such as azetidinyl, pyrrolidinyl, imidazolyl, indolyl, isoazoyl, oxazoyl, triazolyl, tetrazolyl, morpholinyl, piperidinyl, pyrazolyl and piperazinyl.
The term xe2x80x9clower alkylxe2x80x9d (which includes the alkyl part of alkylHet and alkylaryl groups), when used herein, means C1-6 alkyl and includes methyl, ethyl, propyl, butyl, pentyl and hexyl groups. Unless otherwise specified, alkyl groups may, when there is a sufficient number of carbon atoms, be linear or branched, be saturated or unsaturated, be cyclic, acyclic or part cyclic/acyclic, and/or be substituted by one or more halo atoms. Preferred lower alkyl groups for use herein are C1-3 alkyl groups. Alkyl groups which R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27 and R28 may represent, and with which R1, R2, R3, R4, R10, R11, R12, R13, R16, R17, aryl, alkylaryl, alkylHet and Het may be substituted, may, when there is a sufficient number of carbon atoms, be linear or branched, be saturated or unsaturated, be cyclic, acyclic or part cyclic/acyclic, be interrupted by one or more of oxygen, sulfur and optionally alkylated or optionally acylated nitrogen and/or be substituted by one or more halo atom. The terms xe2x80x9clower alkenylxe2x80x9d and xe2x80x9clower alkynylxe2x80x9d, when used herein, include C2-6 groups having one or more double or triple carbon-carbon bonds, respectively. Otherwise, the terms xe2x80x9clower alkenylxe2x80x9d and xe2x80x9clower alkynylxe2x80x9d are defined in the same way as the term xe2x80x9clower alkylxe2x80x9d. Similarly, the term xe2x80x9clower alkylenexe2x80x9d, when used herein, includes C1-6 groups which can be bonded at two places on the group and is otherwise defined in the same way as xe2x80x9clower alkylxe2x80x9d. The term xe2x80x9cacylxe2x80x9d includes C(O)-lower alkyl.
In the above definition, unless otherwise indicated, alkyl, alkoxy and alkenyl groups having three or more carbon atoms, and alkanoyl groups having four or more carbon atoms, may be straight chain or branched chain.
The terms xe2x80x9calkylHetxe2x80x9d and xe2x80x9calkylarylxe2x80x9d include C1-6 alkylHet and C1-6 alkylaryl. The alkyl groups (e.g. the C1-6 alkyl groups) of alkylHet and alkylaryl may, when there is a sufficient number of carbon atoms, be linear or branched, be saturated or unsaturated, and/or be interrupted by oxygen. When used in this context, the terms xe2x80x9cHetxe2x80x9d and xe2x80x9carylxe2x80x9d are as defined hereinbefore. Substituted alkylHet and alkylaryl may have substituents on the ring and/or on the alkyl chain.
Halo groups with which the above-mentioned groups may be substituted or terminated include fluoro, chloro, bromo and iodo and the terms haloalkyl and haloalkoxy include CF3 and OCF3 respectively.
Compounds of general formula (I) can be represented by formulae Ixe2x80x2 and Ixe2x80x3: 
wherein R1, R2, R3, R4 and Q are as defined hereinbefore.
The compounds of formulae (I) may contain one or more chiral centres and therefore can exist as stereoisomers, i.e. as enantiomers or diastereoisomers, as well as mixtures thereof. The invention relates to formation of both the individual stereoisomers of the compounds of formulae (I) and any mixture thereof.
In a first preferred embodiment of the invention a compound of formulae (IA) is prepared. 
Accordingly, in a preferred aspect of the invention there is provided a process for the preparation of a compound of formula (IA). 
comprising reacting a compound of formula (IIA), (IIIA) or (IVA) respectively 
in the presence of xe2x88x92OR3 and a hydroxide trapping agent, or alternatively in the case of compounds of formula (IVA) reacting in the presence of a hydroxide trapping agent and an auxiliary base, wherein OR3 in the case of formation of compound (IA) and (IVA) is CH3(CH2)3Oxe2x80x94 and wherein X in formulae (IIA) and (IIIA) is a leaving group.
Intermediates of the general formula (IIA), (IIIA) and (IVA), where novel, form further aspects of the invention.
As a result of use of the hydroxide trapping agent, a particular advantage of the present process is that a high yield of final product (compounds of formula (I, IA) and intermediate compounds (II, IIA) can be obtained.
In a preferred embodiment compounds of formula (I) can be obtained in good yield without intermediate isolation.
It is most advantageous to form the compounds of formula (I) from intermediates of formula (III) since the cyclisation step (III to II) and the nucleophilic displacement of X by xe2x88x92OR3 (II to I) can be carried out in a one-pot reaction. Furthermore this process can be run at ambient pressure whereas the cyclisation step of the 2 step process can require higher pressures where XH is a lower alkanol, such as methanol, ethanol or isomers of propanol.
In a further aspect of the invention, there is provided a process for the formation of compounds of formula (II) (more particularly IIA wherein X in II/IIA=xe2x80x94OR3) comprising the cyclisation of compounds of formula (III) (more particularly IIIA) wherein X is a leaving group as defined hereinbefore, in the presence of said hydroxide trapping agent. Again, this step benefits from the higher yield provided by using the hydroxide trapping agent.
Of course, the trapping agent technology could be used to form compounds of formula (IV) (more particularly IVA) from compounds of formula (III) (more particularly IIIA) in the presence of xe2x88x92OR3, advantageously up to about 1 molar equivalent of xe2x88x92OR3 (to compounds (III)). If substantially more than 1 equivalent of xe2x88x92OR3 was used, the reaction would proceed through to compounds (I) (more particularly IA).
Preferably the hydroxide trapping agent is an ester.
More preferably said hydroxide trapping agent is an ester of the formula:
TOC(O)W
wherein OT is OR3 as defined hereinbefore or, OT is the residue of a bulky alcohol or a non-nucleophilic alcohol, or TOH is an alcohol which can be azeotropically removed during the reaction;
and C(O)W is the residue of a carboxylic acid.
For example, where X is OEt in compound (IIA) and (IIIA) the ester trapping agent can be n-butyl acetate (i.e. OT=X and C(O)W is a residue of acetic acid), or ethyl acetate or ethyl pivalate, more preferably butyl pivalate (OT=X and C(O)W is the residue of pivalic acid- i.e. a carboxylic acid with no enolisable proton).
In a most preferred process, wherein X is OEt in compound (IIA) or (IIIA) the ester trapping agent is butyl actetate.
Preferably X is selected from the group consisting of optionally substituted arylsulphonyloxy, preferably phenylsulphonyloxy, more preferably a para substituted aryl (phenyl) such as by a C1-C4 alkyl group e.g. p-toluenesulphonyloxy; C1-C4 alkylsulphonyloxy e.g. methanesulphonyloxy; nitro or halo substituted benzenesulphonyloxy preferably para substituted e.g. p-bromobenzenesulfonyloxy or p-nitrobenzenesulphonyloxy; C1-C4 perfluoroalkylsulphonyloxy e.g. trifluoromethylsulphonyloxy; optionally substituted aroyloxy such as benzoyloxy; C1-C4 perfluoroalkanoyloxy such as trifluoroacetyloxy; C1-C4 alkanoyloxy such as acetyloxy; halo; diazonium; C1-C6 primary and secondary alkoxy such as methoxy; quatenaryammonium C1-C4 alkylsulphonyloxy; halosulphonyloxy e.g. fluorosulphonyloxy and other fluorinated leaving groups; and diarylsulphonylamino e.g. ditosyl (NTs2).
Most preferably, for formation of compounds of formula (I) more particularly (IA), X is a C1-C4 alkoxy (advantageously ethoxy or methoxy) or halogen since this lends itself to simpler and cheaper formation of compoundsxe2x80x94for example see Schemes 1 and 3 hereinafter.
An advantage of using labile leaving groups such as chloro or fluoro may be that an inert solvent could then be used rather than R3OH (which will often be more expensive). Thus only a sufficient amount of OR3 (such as from R3OH) as reactant would be required.
xe2x80x94xe2x88x92OR3 can act both as a nucleophile (to displace the leaving group by nucleophilic substitution) and as a base (to bring about the cyclisation).
xe2x80x94xe2x88x92OR3 can be generated in solution from, for example, a salt ZOR3 (wherein Z is a cation) such as a metal salt. More particularly an alkali (such as sodium or potassium) or alkaline earth metal salt of xe2x80x94xe2x88x92OR3 in a suitable solvent would give rise to xe2x80x94xe2x88x92OR3 in solution. For example, potassium butoxide, potassium amylate, KHMDS or NaHMDS in a suitable solvent, under suitable temperature conditions, such as 1-butanol, with intermediate (IIA) or (IIIA) would form compound (IA). In another embodiment, xe2x80x94xe2x88x92OR3 can be formed in situ from R3OH plus an auxiliary base (i.e. a base other than xe2x88x92OR3). However, in another system, ZOR3 could be used in the reaction system with an auxiliary base.
As will be appreciated the solvent in which the reaction takes place can be R3OH or an inert solvent (or a mixture of both). By inert solvent we mean a solvent which will not form a nucleophile under the reaction conditions, or, if a nucleophile is formed it is sufficiently hindered or un-reactive such that it does not substantially compete in the displacement reaction. When R3OH is used as a source of xe2x88x92OR3, then a separate solvent is not essentially required but an (auxiliary) inert solvent (i.e. a solvent other than R3OH) may be used as a co-solvent in the reaction.
Suitable solvents are as follows:
R3OH, a secondary or tertiary C4-C12 alkanol, a C3-C12 cycloalkanol, a tertiary C4-C12 cycloalkanol, a secondary or tertiary (C3-C7 cycloalkyl)C2-C6 alkanol, a C3-C9 alkanone, 1,2-dimethoxyethane, 1,2-diethoxyethane, diglyme, tetrahydrofuran, 1,4-dioxan, toluene, xylene, chlorobenzene, 1,2-dichlorobenzene, acetonitrile, dimethyl sulphoxide, sulpholane, dimethylformamide, N-methylpyrrolidin-2-one, pyridine, and mixtures thereof.
More preferably, the solvent is R3OH, a tertiary C4-C12 alkanol, a tertiary C4-C12 cycloalkanol, a tertiary (C3-C7 cycloalkyl)C2-C6 alkanol, a C3-C9 alkanone, 1,2-dimethoxyethane, 1,2-diethoxyethane, diglyme, tetrahydrofuran, 1,4-dioxan, toluene, xylene, chlorobenzene, 1,2-dichlorobenzene, acetonitrile, dimethyl sulphoxide, sulpholane, dimethylformamide, N-methylpyrrolidin-2-one, pyridine, and mixtures thereof.
Most preferably the solvent is R3OH, which means that xe2x88x92OR3 is formed in situ, such as, in the presence of an auxiliary base. For compound (IA) the solvent is preferably CH3(CH2)3OH (1-butanol).
A wide range of auxiliary bases can be used in the process of the invention. Typically the bases would not substantially compete with xe2x80x94OR3 in the nucleophilic substitution of X (i.e. they would be non nucleophilic) such as by being suitably sterically hindered.
Preferably the auxiliary base is selected from the group consisting of a sterically hindered metal alkoxide base, a metal amide, a metal hydride, metal oxide, metal carbonate and metal bicarbonate.
Examples of suitable alcohol and amine metal salts include metal salts of: a secondary or tertiary C4-C12 alkanol; a C3-C12 cycloalkanol and a secondary or teritary (C3-C8 cycloalkyl)C1-C6 alkanol; a N-(secondary or tertiary C3-C6 alkyl)-N-(primary, secondary or tertiary C3-C6 alkyl)amine; a N-(C3-C8 cycloalkyl)-N-(primary, secondary or tertiary C3-C6 alkyl)amine; a di(C3-C8 cycloalkyl)amine or hexamethyldisilazane; or 1,5-diazabicyclo[4,3,0]non-5-ene and 1,8-diazabicyclo[5,4,0]undec-7-ene.
Examples of suitable metal salts of a tertiary C4-C6 alcohol such as the alkali or alkaline earth metal salts (e.g. Na/K) of t-butanol or t-amyl alcohol, or the base are: potassium t-butoxide, potassium hexamethyldisilazone (KHMDS) or NaHMDS.
More preferably the auxiliary base is a sterically hindered base selected from: metal salts of sterically hindered alcohols or amines; or metal carbonates. Preferred herein are metal carbonates, and advantageously potassium carbonate for the delivery of higher yield, improved impurity profile.
Further examples of suitable carbonate bases for use herein include sodium carbonate, caesium carbonate, lithium carbonate, rubidium carbonate, strontium carbonate, barium carbonate, beryllium carbonate and magnesium carbonate. Preferred for use herein are non-toxic carbonate bases with reasonably rapid reaction rate, in the cyclisation reaction according to the present invention. Potassium carbonate is especially preferred as defined hereinbefore.
Preferably the metal of the salt of ZOR3 and the auxiliary base are independently selected from alkali metals (lithium, sodium, potassium, rubidium, caesium) or alkaline earth metals (beryllium, magnesium, calcium, strontium, barium). More preferably the metal is sodium or potassium and potassium is especially preferred.
To maximise yields, it is further preferred that at least about 1 molecular equivalent of auxiliary base and xe2x80x94OR3 are used in accordance with the invention. If xe2x80x94OR3 also functions as a base (i.e. there is no auxiliary base present) then preferably at least about 2 equivalents of xe2x88x92OR3 are present. Suitably, at least about 1 equivalent of trapping agent (preferably at least about 2 equivalents) is present. Especially preferred for use herein is about 3 equivalents of auxiliary base (preferably potassium carbonate) and at least about 1, preferably at least about 2 and especially about 3 equivalents of trapping agent (preferably butyl acetate).
The temperature of the cyclisation reaction of compounds (III) and (IV) to (I) (such as for the corresponding formation of compound (IA)) is preferably at least about 80xc2x0 C., more preferably about 80 to about 130xc2x0 C., more preferably still about 100 to about 130xc2x0 C. and most preferably about 112xc2x0 C. to about 122xc2x0 C. These temperatures are also applicable for the conversion of compounds (II) to (I), although the temperature in this case could also probably be lower (e.g. about 60xc2x0 C.) since there is no cyclisation taking place.
The reaction temperature attainable to effect the conversion of compounds of formulae (II) and (III) to compounds of formula (I) depends on the solvent, the nature of xe2x88x92OR3 and X. When X is an alkoxy and R3OH is the solvent, preferably XH (such as C1-6 alkoxy) is removed azeotropically (of course the reaction vessel must be configured to distil over the azeotrope mixture) with R3OH by running the reaction at the azeotrope temperature of XH and R3OH. In this way the yield and quality of the final product can be further improved. For example, (where X is an alkoxy) the conversion of compound (IIA), (IIIA) or (IVA) to (IA) is preferably carried out at the azeotrope temperature of the alcohol i.e. XH (preferably methanol or ethanol, most preferably ethanol) and 1-butanol.
Thus according to further preferred embodiments the invention provides:
A process for the synthesis of compound (IA) by reaction of compound (IIA) or (IIIA):
a) with 1-butanol and auxiliary base, preferably potassium butoxide, optionally in an inert solvent such as toluene and in the presence of said trapping agent TOC(O)W; or
b) with ZO(CH2)3CH3 and an auxiliary base in n-butanol or an inert solvent or both, in the presence of said trapping agent; or
c) with ZO(CH2)3CH3 and n-butanol or an inert solvent or both, in the presence of said trapping agent.
Preferably, the trapping agent is BuOC(O)W or CH3OC(O)W wherein C(O)W is a residue of a carboxylic acid (preferably sterically hindered) such as CH3(CH2)3OC(O)CH3 or CH3(CH2)3OC(O)(CH3)3.
To maximise yields, it is further preferred that at least about 1 molecular equivalent of auxiliary base and xe2x80x94OR3 are used in accordance with the invention. If xe2x80x94OR3 also functions as a base (i.e. there is no auxiliary base present) then preferably at least about 2 equivalents of xe2x88x92OR3 are present. Thus to maximise yields of compounds (IA), suitably at least about 1 equivalent of trapping agent (preferably at least about 2 equivalents) is present. With respect to (a) above, preferably there is at least about 2 molecular equivalents of base and at least about 1 molecular equivalent of trapping agent relative to the substrate (more preferably at least about 2.2 and 2.5 respectively). For (b) above, preferably there is at least about 1 molecular equivalent of auxiliary base, trapping agent and ZO(CH2)CH3 relative to the substrate (more preferably at least about 1.2 equivalents of auxiliary base and at least about 2.5 equivalents of trapping agent). For (c) above, preferably there is at least about 2 molecular equivalents of ZO(CH2)3CH3 and at least about 1 equivalent of trapping agent relative to the substrate (more preferably at least about 2 and 2.5 equivalents respectively).
To further improve yields of final product and reduce impurities, preferably C(O)W is the residue of a sterically hindered carboxylic acid and/or a carboxylic acid which does not contain an enolisable proton (e.g. pivalic acid).
The compounds of general formula (III) and (IIIA) may be obtained from readily available starting materials for example, by the routes depicted in the following reaction schemes. Reaction Scheme 1 illustrates for preparation of compounds of compounds of general formula (I) from compounds of formulae (IX) and (XII).
Compound (III) is formed by reaction of intermediate (IX) and compound (XII) in the presence of a coupling agent, such as N,Nxe2x80x2-carbonyldiimidazole and a suitable solvent, such as ethyl acetate. 
wherein R1, R2, R3, R4, X and Q are as defined hereinbefore.
Further suitable conditions for the coupling of compounds of formulae (XII) and (IX) to provide compounds of formula (III) include: conventional amide bond-forming techniques, e.g. via the acyl chloride derivative of (IX) in the presence of up to about a five-fold excess of a tertiary amine such as triethylamine or pyridine to act as scavenger for the acid by-product (e.g. HCl ), optionally in the presence of a catalyst such as 4-dimethylaminopyridine1 in a suitable solvent such as dichioromethane, at from about 0xc2x0 C. to about room temperature. For convenience pyridine may also be used as the solvent.
In particular, any one of a host of amino acid coupling variations may be used. For example, the acid of formula (IX) or a suitable salt (e.g. sodium salt) thereof may be activated using a carbodiimide such as 1,3-dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminoprop-1-yl)carbodiimide optionally in the presence of 1-hydroxybenzotriazole hydrate and/or a catalyst such as 4-dimethylaminopyridine, or by using a halotrisaminophosphonium salt such as for example bromotris(pyrrolidino)phosphonium hexafluorophosphate or by using a suitable pyridinium salt such as 2-chloro-1-methylpyridinium iodide. Either type of coupling is conducted in a suitable solvent such as dichloromethane, tetrahydrofuran or N,N-dimethylformamide, optionally in the presence of a tertiary amine such as triethylamine or N-ethyldiisopropylamine (for example when either the compound of formula (XII), or the activating reagentxe2x80x94for the acid of formula (IX), is presented in the form of an acid addition salt), at from about 0xc2x0 C. to about room temperature. Preferably, from 1 to 2 molecular equivalents of the activating reagent and from 1 to 3 molecular equivalents of any tertiary amine present are employed.
In a further variation, the carboxylic acid function of acid (IX) may first of all be activated using up to about a 5% excess of a reagent such as N,Nxe2x80x2-carbonyldiimidazole in a suitable solvent, e.g. ethyl acetate or butan-2-one, at from about room temperature to about 80xc2x0 C., followed by reaction of the intermediate imidazolide with (XII) at from about 20xc2x0 C. to about 90xc2x0 C.
It will be appreciated that the general formula (XII) can also be represented by the regioisomeric formulae (XIIxe2x80x2) and (XIIxe2x80x3): 
wherein R1 and R2 are as previously defined herein.
In Scheme 1 the compounds of general formula (I) can be prepared from compounds of general formula (III) by: cyclisation directly to a compound of formula (I), route A; exchange of xe2x80x9cXxe2x80x9d for xe2x80x9cQR3 followed by cyclisation of compound (IV) to a compound of formula (I), route B; or by cyclisation to form a compound (II) followed by exchange of xe2x80x9cXxe2x80x9d for xe2x80x9cOR3xe2x80x9d, route C. The cyclisation of route A includes both cyclisation where X=OR3 as well as cyclisation with alkoxide exchange where X is exchanged for OR3. Routes A, B and C are in a preferred process according to the present invention carried out in a one-pot process without isolation of intermediate compounds, such as for example compounds (II) or (IV).
Reaction Scheme 2 illustrates the preparation of compounds of general formula (IX) starting from the commercially available material, 2-hydroxynicotinic acid. 
In the compounds of Scheme 2, X and R4 are as hereinbefore defined. P is a group which can undergo an oxidative addition reaction with Palladium (0), such as for example halogen, trifluoromethanesulfonate, perfluoroethane sulfonate, diazonium salts and is preferably F, Cl, Br or I, more preferably Br or I. V is any suitable carboxylic acid protecting group such as: C1-C4 alkyl esters, preferably ethyl or methyl esters; aryl groups such as benzyl; or a silicon protecting group such as a trimethylsilyl (TMS) group.
As illustrated in Scheme 2, where not commercially available, the intermediate of formula (V) can be formed from commercially available starting materials such as 2-chloronicotinic acid or 2-hydroxynicotinic acid or a salt thereof by routine synthetic methods such as are exemplified hereinafter in the preparations section.
Intermediate compounds of formula (IX) wherein X=OR3a wherein OR3a is a different alkoxy group from OR3 wherein R3a is a C1-C6 alkyl group, preferably a C1-C4 alkyl group and R4 is as defined hereinbefore can be formed from compounds of formula (VIII) (wherein X=OR3a and R4 are as defined for (IX) and V is as defined hereinbefore) by hydrolysis, when V is an alkyl or aryl group, (IX) is preferably formed via base hydrolysis with metal hydroxide, more preferably with sodium hydroxide. Where V is a benzyl or silyl group, (IX) is formed via hydrogenation.
Compounds of formula (VIII) wherein X=OR3a and R4 and V are as defined herein before, can be formed from compounds of formula (VII) (wherein X=OR3a and V are as defined for (VII) and P is as defined hereinbefore) via a substitution reaction (wherein group P is exchanged for the desired R4 moiety), and preferably wherein such substitution reaction is a metal-mediated reaction. According to a preferred process said conversion is affected via acylation under Heck conditions as exemplified hereinafter.
Accordingly the present invention provides a process for the conversion of compound (VII) (wherein P=Br or 1, wherein X=OEt and wherein V is as defined hereinbefore) to compound (VIII) (wherein R4=C(O)CH3 and X=OEt and V is as defined hereinbefore) such as via reaction with butylvinyl ether and triethylamine in a suitable solvent, such as for example acetonitrile, dimethyl formamide (DMF), dimethyl acetamide (DMAC), N-methyl pyrrolidone (NMP) or water, under reflux conditions and at atmospheric pressure wherein said reaction is carried out in the presence of a suitable catalyst such as palladium acetate and a ligand such as tri-o-tolyl phosphine wherein the ratio of compound (VII) to acylating agent is about 1:15, preferably about 1:8, more preferably about 1:10 molecular equivalents and wherein the ratio of compound (VII) to base is about 1:2.0, preferably about 1:1.5 molecular equivalents and wherein the ratio of compound (VII) to catalyst in about 1:0.25, preferably about 1:0.16 molecular equivalents. To ensure appropriate conversion of the non-isolated intermediate enol-ether compound VIIIxe2x80x2 to the desired ester VIII the reaction should have an aqueous acidic work-up. 
wherein X and V are as defined hereinbefore and wherein R5 is a C1-C5 alkyl group, preferably C1-C4 alkyl and especially butyl.
Compounds of formula (VII) wherein X OR3a and V and P are as defined hereinbefore, and preferably wherein X=(C1-C4) primary or secondary alkoxy and P is a halogen, can be formed from compounds of formula (VI) (wherein X and P are as defined for (VII)) in an esterification/protection reaction via treatment with a suitable acid catalyst and an alcohol of formula Vxe2x80x94OH, or treatment with a suitable base and an alkylating agent wherein V is as defined hereinbefore, and wherein V is preferably C1-C4 alkyl. Preferred conditions wherein X=OEt; Vxe2x80x94OH=CH3xe2x80x94OH include: treatment with an HCl/H2SO4 mixture; or treatment with H2SO4; or treatment with ethyl iodide and cesium cabonate.
Compounds of formula (VI) (wherein X=OR3a and P is as previously defined) can be formed from compounds of formula (V) wherein X=OR3a, via a halogenation reaction such as bromination with a suitable electrophilic halogenation agent i.e. N-bromosuccinamide.
It is possible to undertake the three step conversion of (VI) to (IX) (more particularly (VIA) to (IXA), see Scheme 5 hereinafter) in a single step.
Thus according to a highly preferred process of the invention and as illustrated in Scheme 2, compounds of general formula (VI) can be transformed directly into compounds of general formula (IX). Such direct transformation reactions proceed via a non isolated intermediate compound of general formula VIxe2x80x2 as illustrated below: 
wherein X is as defined herein before.
In such a highly preferred process compounds of formula (IX) can be prepared directly from compounds of formula (VI) in a one-step reaction. Suitable reagents for such direct conversion of compounds of formula (VI) to compounds of formula (IX) wherein X=OR3a, preferably wherein X=OEt, and wherein P=a halogen, preferably Br, include using butyl vinyl ether and triethylamine in acetonitrile solvent at reflux temperature and at ambient/atmospheric pressure in the presence of catalyst such as palladium acetate and ligand such as tri-o-tolyl phosphine. For such reactions suitable reagent amount are (i) the ratio of base to compound (VI) is more than about 1.5:1, preferably more than about 2.0:1 and more preferably about 2.5:1 molecular equivalents and/or; (ii) the ratio of acylating agent to compound (VI) is about 2.5:1 to about 5:1, preferably about 2.5:1 to about 3.5:1 and especially about 3:1 molecular equivalents. Especially preferred herein for the provision of high yield of (XI) are such reactions wherein in addition to the aforementioned preferred ratios of acid (VI) to base and/or acylating agent, the ratio of acid (VI) to catalyst is about 1:0.04 molecular equivalents.
It is especially surprising that the above highly preferred conditions furnished higher yields of (IX) versus similar reactions where a higher catalyst level was utilised.
Following the initial reaction of compound (VI) with the base, acylating agent and catalyst in an appropriate solvent it is necessary that the reaction mixture is subjected to an aqueous acidic work-up in order to furnish the desired compound of formula (IX) rather than the intermediate enol-ether (VIxe2x80x2) as detailed hereinbefore.
Reaction Scheme 3 illustrates the preparation of compounds of general formula (XI). 
wherein R1 and R2 are as defined hereinbefore.
With reference to Scheme 3 compounds of formula (XII) can be formed from compounds of formula (XI) via a suitable reduction reaction such as with palladium on charcoal and hydrogen, under pressure where necessary. Compounds of formula (XI) can be formed from compounds of formula (X) via a suitable alkylation, arylation or acylation reaction.
Reaction Schemes 4 to 6 provide the corresponding intermediate compounds and transformations for the preparation of highly preferred compound (IA).
Scheme 4 illustrates a preferred process for the coupling of preferred compounds (IXA) and (XIIA) to provide compound of formula (IIIA) which are then cyclised to provide the compound of formula (IA) according to the process of the present invention. 
Reaction Scheme 5 illustrates a preferred process for the preparation of compounds of formula (IXA). 
Scheme 5 illustrates a preferred embodiment for the formation of compound (IX) as generally described in Scheme 2, wherein X is an alkoxy (and so X in compound VA represents OR3a), more preferably a C1-6 primary or secondary alkoxy, such as ethoxy.
Compounds of the general formula (IXA) are prepared according to methods shown in Examples section hereinafter.
According to a highly preferred process herein compound (IXA) is prepared directly from compound (VIA) by reaction with acylating agent, base and catalyst wherein the ratio of compound (VIA):acylating agent:base:catalyst is about 1:3:2.5:0.04 molecular equivalents. In an especially preferred process the acylating agent is butyl vinyl ether, the base is triethylamine, the catalyst is Pd(OAc)2, the solvent is acetonitrile and the ligand is tri-o-tolyl phosphine and the reaction is carried out under reflux conditions at atmospheric pressure. Such preferred process is illustrated at preparation 1(b) hereinafter.
Reaction Scheme 6 illustrates the preparation of compounds of general formula (XIIA) as generally detailed in Scheme 3. 
Compounds of formula (XIIA) can be formed from compounds of formula (XIA) via hydrogenation such as via treatment with palladium/charcoal and hydrogen and as exemplified herein at preparation 9 hereinafter.
Compounds of formula (XIA) can be formed from compounds of formula (XIDP) via a two stage process of: (i) amination (to prepare an intermediate imine of general formula (XIDPxe2x80x2) as illustrated below: 
such as via treatment with acetaldehyde or a synthetic equivalent followed by; (ii) reduction such as with Na(OAc)3 BH to furnish the desired compound of formula (XIA) and as exemplified herein at preparation 8 hereinafter.
Compounds of formula (XIDP) can be formed from compounds of formula (XIP) via de-protection of the N-protecting benzhydryl group using suitable de-protection conditions such as exemplified at preparation 7 hereinafter.
Compounds of formula (XIP) can be formed from compounds of formula (XA) according to the processes at preparations 6(a) and 6(b) hereinafter. The process of preparation 6(b) is particularly preferred herein as it provides higher yields.
According to a further aspect of the process hereinbefore described for the preparation of compounds of the general formula (XIA), such compounds can be prepared from compounds (XA) via a xe2x80x9cone-stepxe2x80x9d process via reaction with the compound: 
wherein such reaction takes place in a suitable non nucleophilic solvent, such as for example THF.
According to a particularly preferred process herein compounds of the general formula (XIA) can be prepared directly from compounds of the formula (XA). An advantage of such direct transformation is process efficiency.
Compound (IIIA) is formed by reaction of intermediate (IX) and 4-Amino-5-ethyl-1(2-ethyl-azetidinyl)-1H-pyrazole-3-carboxamide (compound XII) in the presence of a coupling agent, such as 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride and where desirable also in the presence of a base and/or an accelerator. In one example of a coupling system, the carboxylic acid function of (VIA) is first of all activated using molar equivalent of a reagent such as N,Nxe2x80x2-carbonyldimidazole (as coupling agent) in a suitable solvent, e.g. ethyl acetate, at from about room temperature to about 80xc2x0 C., followed by reaction of the intermediate imidazolide with (XIIA) at from about 35 to about 80xc2x0 C. In another example, intermediate (IXA) could be coupled to the pyrazole (XIIA) in the presence of 1-hydroxybenzotriazole, triethylamine and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride.
It will be appreciated that salts of compounds (I) and (IA) of Schemes 1 and 4 can be formed in accordance with the invention by converting the relevant compound to a salt thereof (either in situ or as a separate step). For example base addition salts of the compounds of formulae (VI) and (XI) can be formed and can be utilised in accordance with the process of the present invention. Also the acid addition salts of the compounds of formulae (I) and (IA) can be formed in accordance with the invention.
By way of illustration, acid addition salts of compounds of formula (I) (more particularly (IA)) can be formed by reacting a compound of formula (I) with an equimolar or excess amount of acid. The salt may then be precipitated out of solution and isolated by filtration or the solvent can be stripped off by conventional means.
The pharmaceutically or veterinarily acceptable salts of the compounds of formulae (I) and (IA) which contain a basic centre are, for example, non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulphuric and phosphoric acid, with carboxylic acids or with organo-sulphonic acids. Examples include the HCl, HBr, Hl, sulphate or bisulphate, nitrate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, saccarate, fumarate, maleate, lactate, citrate, tartrate, gluconate, camsylate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoate salts. Compounds (I) and (IA) can also provide pharmaceutically or veterinarily acceptable metal salts, in particular non-toxic alkali and alkaline earth metal salts, with bases. Examples include the sodium, potassium, aluminium, calcium, magnesium, zinc and diethanolamine salts. For a review on suitable pharmaceutical salts see Berge et al J. Pharm, Sci., 66, 1-19, 1977.
The pharmaceutically acceptable solvates of compounds (I) and (IA) include the hydrates thereof.
Suitable protecting groups for use in accordance with the invention can be found in xe2x80x9cProtecting Groupsxe2x80x9d edited by P. J. Kocienski, Thieme, N.Y., 1994 xe2x80x94see particularly chapter 4, page 118-154 for carboxy protecting groups; and xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d 2nd edition, T. W. Greeene and P. G. M. Wutz, Wileyxe2x80x94Interscience (1991)xe2x80x94see particularly chapter 5 for carboxy protecting groups.